This project provides support and enabling methodology for a multi-investigator effort to develop transcriptional gene silencing and activation as a new RNA-based strategy for controlling the infectivity of HIV-1. We will take advantage of exciting preliminary results that show that protein nanoparticles derived from the Q[bacteriophage can be chemically modified to carry multiple copies of the active RNA molecules, to target cells by virtue of a specifically engineered ligand-receptor interaction, and to deliver the active RNA to elicit the desired functional result. Many aspects of this platform technology remain to be optimized; such experiments and strategies are proposed here. They include the further use of unnatural amino acids in the nanoparticle structure to allow controlled chemical conjugation, the introduction of cleavable linkers to allow for RNA release, the introduction of polycationic species for charge compensation, the exploration of additional targeting ligands, and the cellular effects of all of these modifications. This work represents an attempt to address a longstanding challenge in oligonucleotide delivery, one that is extremely difficult to master on the scale required to implement RNA interference in vivo. However, the characteristics of transcriptional gene silencing/activation make it necessary to deliver smaller amounts of active agents, and thus these studies seek to further improve and study a promising protein nanoparticle delivery approach.